DESCRIPTION: Necrotic cell death is the initial pathologic change in muscle of patients with muscular dystrophy. Even for the most common forms of muscular dystrophy, those due to defects in the dystrophin gene, the cause of muscle necrosis remains unknown despite a wealth of information on the dystrophin gene, its message, and its protein product. The broad, long-term objectives of this work are: 1) to understand the pathogenetic mechanisms that lead to cell death in muscular dystrophies; and 2) to study therapeutic approaches to intervene in those biochemical pathways to prevent muscle degeneration. The primary hypothesis of this proposal (the free radical hypothesis) is that dystrophin deficiency renders muscle more susceptible to oxidative injury, and thus normal levels of oxidative stress result in membrane damage sufficient to cause muscle fiber necrosis. The principle investigator proposes to test this hypothesis, in vitro and in vivo, using a mouse strain with dystrophin deficiency (the mdx strain). The specific aims of this proposal are: 1) to examine dystrophin-deficient muscle in vivo for signs of oxidative damage: studies of the pre-necrotic state; (oxidative injury and cellular responses to that injury will be measured in mdx mouse muscle just prior to the onset of necrosis); 2) to study, in vitro, the susceptibilities of normal and dystrophin-deficient muscle to oxidative stress and the effect of different forms of dystrophin in protecting muscle cells against oxidative injury (myotube cultures of normal and dystrophin-deficient muscle will be studied in assays of cell injury and cell death); and 3) to test the effects of enhanced antioxidant engineered by breeding with transgenic strains to express higher levels of an antioxidant enzyme, or mdx mice will be treated with pharmacologic antioxidant agents, and disease progression will be assessed histologically and biochemically.